A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate

Mounira Chalabi-Dchar; Tanguy Fenouil; Christelle Machon; Anne Vincent; Frédéric Catez; Virginie Marcel; Hichem C Mertani; Jean-Christophe Saurin; Philippe Bouvet; Jérôme Guitton; Nicole Dalla Venezia; Jean-Jacques Diaz

doi:10.1093/narcan/zcab032

A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate

NAR Cancer ◽

10.1093/narcan/zcab032 ◽

2021 ◽

Vol 3 (3) ◽

Author(s):

Mounira Chalabi-Dchar ◽

Tanguy Fenouil ◽

Christelle Machon ◽

Anne Vincent ◽

Frédéric Catez ◽

...

Keyword(s):

Cell Fate ◽

Ribosomal Rna ◽

Mode Of Action ◽

Rna Modifications ◽

Cell Plasticity ◽

Historical Knowledge ◽

Cytotoxic Effects ◽

Translational Activity ◽

Pancreatic Cancers ◽

Patients Experience

Abstract 5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse.

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Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

Nature Communications ◽

10.1038/s41467-021-21117-3 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Erik Jung ◽

Matthias Osswald ◽

Miriam Ratliff ◽

Helin Dogan ◽

Ruifan Xie ◽

...

Keyword(s):

Tumor Cell ◽

Cell Fate ◽

Cell Plasticity ◽

Cytotoxic Effects ◽

Perivascular Niche ◽

Tumor Cell Plasticity ◽

Preferential Location ◽

Specific Contribution ◽

Live Mouse

AbstractBoth the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy—independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

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Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

10.21203/rs.3.rs-39208/v1 ◽

2020 ◽

Author(s):

Erik Jung ◽

Matthias Osswald ◽

Miriam Ratliff ◽

Ruifan Xie ◽

Sophie Weil ◽

...

Keyword(s):

Tumor Cell ◽

Cell Fate ◽

Cell Plasticity ◽

Cytotoxic Effects ◽

Perivascular Niche ◽

Tumor Cell Plasticity ◽

Preferential Location ◽

Specific Contribution ◽

Live Mouse

Abstract Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches could be determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitated resistance against cytotoxic effects of radiotherapy and chemotherapy - independently of each other, but with additive effects. Perivascular glioblastoma cells were particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depended on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induced resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

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lncRNAs in development and disease: from functions to mechanisms

Open Biology ◽

10.1098/rsob.170121 ◽

2017 ◽

Vol 7 (7) ◽

pp. 170121 ◽

Cited By ~ 73

Author(s):

M. Joaquina Delás ◽

Gregory J. Hannon

Keyword(s):

Differential Expression ◽

Cell Fate ◽

Mode Of Action ◽

Non Coding Rnas

Differential expression of long non-coding RNAs (lncRNAs) during differentiation and their misregulation in cancer highlight their potential as cell fate regulators. While some example lncRNAs have been characterized in great detail, the functional in vivo relevance of others has been called into question. Finding functional lncRNAs will most probably require a combination of complementary approaches that will greatly vary depending on their mode of action. In this review, we discuss the different tools available to dissect genetically lncRNA requirements and how each is best suited to studies in particular contexts. Moreover, we review different strategies used to select candidate lncRNAs and give an overview of lncRNAs described to regulate development and cancer through different mechanisms.

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Chromatin Dynamics in Intestinal Epithelial Homeostasis: A Paradigm of Cell Fate Determination versus Cell Plasticity

Stem Cell Reviews and Reports ◽

10.1007/s12015-020-10055-0 ◽

2020 ◽

Vol 16 (6) ◽

pp. 1062-1080

Author(s):

Jérémie Rispal ◽

Fabrice Escaffit ◽

Didier Trouche

Keyword(s):

Signaling Pathways ◽

Cell Fate ◽

Chromatin Modification ◽

Intestinal Cell ◽

Intestinal Epithelial ◽

Cell Plasticity ◽

Chromatin Dynamics ◽

Irritable Bowel ◽

The Many

AbstractThe rapid renewal of intestinal epithelium is mediated by a pool of stem cells, located at the bottom of crypts, giving rise to highly proliferative progenitor cells, which in turn differentiate during their migration along the villus. The equilibrium between renewal and differentiation is critical for establishment and maintenance of tissue homeostasis, and is regulated by signaling pathways (Wnt, Notch, Bmp…) and specific transcription factors (TCF4, CDX2…). Such regulation controls intestinal cell identities by modulating the cellular transcriptome. Recently, chromatin modification and dynamics have been identified as major actors linking signaling pathways and transcriptional regulation in the control of intestinal homeostasis. In this review, we synthesize the many facets of chromatin dynamics involved in controlling intestinal cell fate, such as stemness maintenance, progenitor identity, lineage choice and commitment, and terminal differentiation. In addition, we present recent data underlying the fundamental role of chromatin dynamics in intestinal cell plasticity. Indeed, this plasticity, which includes dedifferentiation processes or the response to environmental cues (like microbiota’s presence or food ingestion), is central for the organ’s physiology. Finally, we discuss the role of chromatin dynamics in the appearance and treatment of diseases caused by deficiencies in the aforementioned mechanisms, such as gastrointestinal cancer, inflammatory bowel disease or irritable bowel syndrome.

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Resveratrol Targets Sphingolipid Metabolism to Induce Growth Inhibition in FLT3 ITD Acute Myeloid Leukemia

Proceedings ◽

10.3390/proceedings2019040004 ◽

2019 ◽

Vol 40 (1) ◽

pp. 4

Author(s):

Ersöz ◽

Adan

Keyword(s):

Growth Inhibition ◽

Cell Fate ◽

De Novo ◽

Therapeutic Potential ◽

Annexin V ◽

Sphingolipid Metabolism ◽

Ceramide Synthase ◽

Cytotoxic Effects ◽

Sphingosine 1 Phosphate ◽

First Time

Sphingolipids are important signaling lipids which play crucial roles to determine the cell fate. Ceramide, apoptotic central molecule of sphingolipid metabolism, which is produced through de novo pathway by serine palmitoyl transferase (SPT) and can be converted to antiapoptotic sphingosine-1-phosphate (S1P) and glucosyl ceramide (GC) by sphingosine kinase (SK) and glucosyl ceramide synthase (GCS), respectively. It is aimed to investigate therapeutic potential of resveratrol on FLT3-ITD (Internal Tandem Duplication) AML cells and to identify potential mechanism behind resveratrol-mediated growth inhibition by targeting of ceramide metabolism. The cytotoxic effects of resveratrol, SPT inhibitor (myricoin), SK-1 inhibitor (SKI II), GCS inhibitor (PDMP), resveratrol: SPT inhibitor, resveratrol: SK-1 inhibitor and resveratrol: GCS inhibitor combinations on MOLM-13 and MV4-11 FLT3 ITD AML cells were investigated by cell proliferation assay. Apoptosis was evaluated by annexin V/PI double staining. There were synergistic cytotoxic effects of resveratrol with co-administration of SPT inhibitor, SK-1 inhibitor and GCS inhibitor and apoptosis was synergistically induced for resveratrol and its combinations. This preliminary data showed for the first time that resveratrol might inhibit the growth of FLT3 ITD AML cells through targeting ceramide metabolism.

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Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity

Cancers ◽

10.3390/cancers12102792 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2792

Author(s):

Provas Das ◽

Joseph H. Taube

Keyword(s):

Cell Fate ◽

Cancer Cell ◽

Current Knowledge ◽

Carcinoma Cells ◽

Aberrant Methylation ◽

Cellular Plasticity ◽

Cell Plasticity ◽

Stages Of Development ◽

Histone 3 ◽

Cancer Initiation

Properly timed addition and removal of histone 3 lysine 27 tri-methylation (H3K27me3) is critical for enabling proper differentiation throughout all stages of development and, likewise, can guide carcinoma cells into altered differentiation states which correspond to poor prognoses and treatment evasion. In early embryonic stages, H3K27me3 is invoked to silence genes and restrict cell fate. Not surprisingly, mutation or altered functionality in the enzymes that regulate this pathway results in aberrant methylation or demethylation that can lead to malignancy. Likewise, changes in expression or activity of these enzymes impact cellular plasticity, metastasis, and treatment evasion. This review focuses on current knowledge regarding methylation and de-methylation of H3K27 in cancer initiation and cancer cell plasticity.

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MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate

Development ◽

10.1242/dev.091082 ◽

2013 ◽

Vol 140 (16) ◽

pp. 3311-3322 ◽

Cited By ~ 7

Author(s):

M.-E. Mathieu ◽

C. Faucheux ◽

C. Saucourt ◽

F. Soulet ◽

X. Gauthereau ◽

...

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Cell Fate ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cell ◽

Embryonic Cell ◽

Cell Plasticity ◽

Stem Cell Plasticity

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Studies on the cytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarin

Cancer Letters ◽

10.1016/s0304-3835(97)00331-5 ◽

1997 ◽

Vol 118 (2) ◽

pp. 201-211 ◽

Cited By ~ 93

Author(s):

Denise Egan ◽

Paraic James ◽

Deirdre Cooke ◽

Richard O'Kennedy

Keyword(s):

Mode Of Action ◽

Cytotoxic Effects

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Epitranscriptomic modifications in acute myeloid leukemia: m6A and 2′-O-methylation as targets for novel therapeutic strategies

Biological Chemistry ◽

10.1515/hsz-2021-0286 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Cornelius Pauli ◽

Michael Kienhöfer ◽

Stefanie Göllner ◽

Carsten Müller-Tidow

Keyword(s):

Acute Myeloid Leukemia ◽

Ribosomal Rna ◽

Myeloid Leukemia ◽

Current Knowledge ◽

Therapeutic Strategies ◽

Therapeutic Interventions ◽

Rna Modifications ◽

Novel Therapeutic Strategies ◽

Acute Myeloid

Abstract Modifications of RNA commonly occur in all species. Multiple enzymes are involved as writers, erasers and readers of these modifications. Many RNA modifications or the respective enzymes are associated with human disease and especially cancer. Currently, the mechanisms how RNA modifications impact on a large number of intracellular processes are emerging and knowledge about the pathogenetic role of RNA modifications increases. In Acute Myeloid Leukemia (AML), the N 6-methyladenosine (m6A) modification has emerged as an important modulator of leukemogenesis. The writer proteins METTL3 and METTL14 are both involved in AML pathogenesis and might be suitable therapeutic targets. Recently, close links between 2′-O-methylation (2′-O-me) of ribosomal RNA and leukemogenesis were discovered. The AML1-ETO oncofusion protein which specifically occurs in a subset of AML was found to depend on induction of snoRNAs and 2′-O-me for leukemogenesis. Also, NPM1, an important tumor suppressor in AML, was associated with altered snoRNAs and 2′-O-me. These findings point toward novel pathogenetic mechanisms and potential therapeutic interventions. The current knowledge and the implications are the topic of this review.

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